Model prediction of each VSD contribution to pore opening. The intrinsic voltage dependence of the pore is extremely rightward-shifted (no VSDs coupled; gray curves). The activation of each voltage sensor provides an energetic contribution to the stabilization of the open state of the channel, resulting in an overall facilitation of channel opening (leftward shift of the G(V); dotted colored lines). Please note that VSD-I activation caused the largest leftward shift of the G(V) (A; blue dotted line), with a smaller contribution of VSD-IV (D; orange dotted line) and negligible roles of VSD-II (B) and VSD-III (C).